The chemokine receptors CXCR4 and CCR5 have been identified as major co-receptors for HIV-1 entry into CD4+ T cells. The majority of primary HIV-1 isolates in early disease use CCR5 as a co-receptor, whereas during disease progression with the emergence of SI (syncytium inducing) viruses, CXCR4 is also used. We performed a cross-sectional study in which we evaluated the expression of two HIV-1 co-receptors, CCR5 and CXCR4, in whole blood samples taken from HIV-1-infected and uninfected individuals. We demonstrate that CXCR4 on CD4+ and CD8+ T cells, and CD14+ monocytes is significantly down-regulated and CCR5 expression on CD4+ T cells is up-regulated in HIV-infected individuals compared to uninfected controls. Co-receptor expression correlated with the level of cellular activation in-vivo in both HIV-infected and uninfected individuals; CXCR4 was expressed predominantly on quiescent (HLA-DR-) T cells and CCR5 was expressed predominantly on activated (HLA-DR+) T cells. Lower expression of CXCR4 and higher expression of CCR5 on CD4+ T cells correlated with advancing disease. Also, a tendency for greater activation of CXCR4+ CD4+ T cells in patients with advanced disease was observed. Patients who harbored SI viruses, however, could not be distinguished from those who harbored non-syncytial inducing(NSI) viruses on the basis of cellular co-recpetor expression.